Compounds and methods for lowering the abuse potential and extending the duration of action of a drug

ABSTRACT

The abuse potential of a bioavailable drug such as an opiate analgesic agent is reduced and its duration of action is extended by converting it to a poorly absorbed ester prodrug or other prodrug derivative prior to formulation. Unlike many existing sustained release formulations of active pharmaceutical agents wherein an active pharmaceutical agent can be released by chewing, crushing, or otherwise breaking tablets or capsule beads containing the active pharmaceutical agent, such mechanical processing of tablets or capsule beads containing a prodrug of this invention neither releases the active drug nor compromises the controlled conversion of prodrug to drug. Moreover, tablets and capsule beads containing prodrugs of this invention or other drugs can be formulated with a sufficient amount of a thickening agent such as hydroxypropylmethylcellulose or carboxymethylcellulose to impede inappropriate intravenous and nasal administration of formulations that are not indicated for these modes of administration.

This application is a divisional, which claims the benefit under 35U.S.C. § 120 of U.S. patent application Ser. No. 10/800,898, filed Mar.15, 2004, which claimed the benefit of U.S. Provisional Application No.60/454,253 filed Mar. 13, 2003; each of which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

The duration of action of orally administered drugs in tablets orcapsules is often extended by utilizing a controlled release method ofdelivery wherein an active pharmaceutical agent is coated and/orencapsulated and/or otherwise entrapped by a material that delaysdissolution of the active agent. This method of delivery requires alarger amount of active agent than immediate release formulations toallow for a longer duration of action. Intentional or unintentionalmechanical processing of such controlled release tablets or capsulebeads could compromise the controlled release action of suchformulations, and thereby may produce, subsequent to administration,toxic levels of active drug. Thus, for example, controlled releasemorphine marketed under the name Avinza® and controlled releaseoxycodone marketed under the name OxyContin® contain sufficient opioidto produce powerful euphoria as well as potentially fatal respiratorydepression when controlled release tablets or capsule beads are chewed,crushed, ground, or otherwise broken so as to compromise the controlledrelease action of the formulation as indicated by the black box warningon the package insert for OxyContin® and Avinza®).

Because one can easily achieve a powerful morphine-like high after oralintravenous or nasal administration of crushed tablets or capsule beads,the abuse potential of these formulations is great. Consequently, abuseof OxyContin® has become a serious problem as evidenced by medicalexaminer reports that attribute several hundred deaths per year to abuseof sustained release oxycodone, and as evidenced by the substantialfraction of new enrollees in methadone treatment centers who indicatesustained release oxycodone as their primary drug of abuse.

Numerous U.S. Publications (e.g. U.S. Pat. Nos. 6,475,494; 6,451,806;6,375,957; 6,277,384; 6,228,863; 4,785,000; 4,769,372; 4,661,492;4,457,933; and 3,966,940) describe the addition of an opioid antagonistsuch as naloxone or naltrexone to formulations of opioid agonists forpurposes of lowering their abuse potential. Typically this approachrelies on the use of a form and/or amount of antagonist that is able toneutralize the opioid agonist when the contents of crushed tablets areadministered parenterally, but not when unbroken tablets areadministered orally as medically indicated. An oral formulation of theopioid pentazocine marketed under the name TALWIN®Nx contains naloxoneto impede abusive intravenous administration. Abusive intravenousadministration of TALWIN Nx, however, may cause harmful withdrawalsyndromes in narcotic dependent individuals. Although Talwin Nx has alower potential for abusive parenteral administration than previouslymarketed oral pentazocine formulations containing no antagonist, itstill is subject to abusive oral administration. U.S. documents U.S.Pat. No. 5,149,538 and U.S. Pat. No. 5,236,714 discuss the use ofantagonists to impede abuse of opiod formulations that are medicallyindicated for transdermal administration. U.S. documents U.S. Pat. No.4,457,933 and U.S. Pat. No. 6,475,494 disclose that the presence of anappropriate amount of an opioid antagonist in an agonist formulationmedically indicated for oral administration may also reduce abusive oraladministration of that formulation. This reduction has been attributed(U.S. document U.S. Pat. No. 6,475,494) to an aversive effect of theantagonist in physically dependent individuals. WO 02094254 describesaddition of an appropriate amount of capsaicin to an oral formulation todeter abusers from crushing prescription pharmaceutical tablets forabusive snorting, injection or ingestion.

Other side effects of opioid analgesics include gastrointestinaldysfunction caused by the opioids binding to the μ receptors present inthe gastrointestinal tract. The side-effects in the stomach include areduction in the secretion of hydrochloric acid, decreased gastricmotility, thus prolonging gastric emptying time, which can result inesophageal reflux. Passage of the gastric contents through the duodenummay be delayed by as much as 12 hours, and the absorption of orallyadministered drugs is retarded. In the small intestines the opioidanalgesics diminish biliary, pancreatic and intestinal secretions anddelay digestion of food in the small intestine. Resting tone isincreased and periodic spasms are observed. The amplitude of thenonpropulsive type of rhythmic, segmental contractions is enhanced, butpropulsive contractions are markedly decreased. Water is absorbed morecompletely because of the delayed passage of bowel contents, andintestinal secretion is decreased increasing the viscosity of the bowelcontents. Propulsive peristaltic waves in the colon are diminished orabolished after administration of opioids, and tone is increased to thepoint of spasm. The resulting delay in the passage of bowel contentscauses considerable desiccation of the feces, which, in turn retardstheir advance through the colon. The amplitude of the non-propulsivetype of rhythmic contractions of the colon usually is enhanced. The toneof the anal sphincter is greatly augmented, and reflex relaxation inresponse to rectal distension is reduced. These actions, combined withinattention to the normal sensory stimuli for defecation reflex due tothe central actions of the drug, contribute to opioid-inducedconstipation.

Although addition of opioid antagonists and other aversive agents topharmaceutical tablets or capsules may well prevent abuse, they may alsodo harm. Thus, there is a need for the developments of a new class ofopioid analgesics that are abuse resistant and have lower propensity toagonize the μ receptors in the gastrointestinal tract than the opioidanalgesics present in the prior art.

SUMMARY OF THE INVENTION

The present invention fills this need by providing for a method forproducing non-naturally occurring prodrugs of analgesic drugs that bindto μ opioid receptors that has a low abuse potential, an extendedduration of action and reduced GI side-effects. Also claimed areprodrugs of analgesic drugs that have lower binding affinity to μ opioidreceptors than the analgesic drug. The method of this invention involvesconverting, prior to formulation, a bioavailable analgesic drug thatbinds to a μ opioid receptor to a prodrug that limits the accessibilityof the drug to its target tissue. Unlike many existing sustained releasetablet and capsule formulations of active pharmaceutical agents whereinthe active pharmaceutical agent can be released by chewing, crushing, orotherwise breaking tablets or capsule beads containing the activepharmaceutical agent, such mechanical processing of tablet or capsuleformulations of prodrugs of this invention neither releases the agentnor compromises the conversion of inactive prodrug to active drug.

The prodrug compositions of this invention limit the bioavailability ofthe drug, because the prodrug is poorly absorbed by the blood afteradministration by the medically indicated route of administration or incases wherein the prodrug is absorbed by the blood or in cases whereinthe prodrug is injected directly into the blood stream the prodrug ismore poorly absorbed by or has a smaller therapeutic effect on thetarget tissue than the drug.

This invention includes but is not limited to ester prodrug compositionsof bioavailable opioid analgesic agents wherein an alkyl or cyclicalkyl, or phenolic or enolic hydroxyl group of the drug is covalentlylinked to an acyl group, and wherein the acyl group is chosen so as tolimit the bioavailability of and rate of conversion of prodrug to drugso as to produce the desired duration of action of the drug.

Also included in this invention is a method involving the use of athickening agent such as hydroxypropylmethylcellulose orcarboxymethylcellulose to impede intranasal or intravenousadministration of formulations of the prodrugs of this invention orother formulations of medications that are not medically indicated forintranasal or intravenous administration.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Receptor Binding Affinity is the binding strength that a molecule has toa receptor. Affinity is measured by the equilibrium dissociationconstant of the drug-receptor complex (denoted K_(d)); the fraction ofreceptors occupied by the drug is determined by the concentration ofdrug and K_(d). See Goodman & Gilman's “The Pharmacological Basis ofTherapeutics” 10 ed., McGraw-Hill, New York, N.Y., 2001, pp. 39-40.

μ Opioid Receptor is the primary receptor to which the opioid analgesicdrugs bind to produce their analgesic effects. The opioid analgesicdrugs are morphine-related drugs. Examples of opioid analgesics includemorphine, hydromorphone, oxymorphone, levorphanol, levallorphan codeine,hydrocodone and oxycodone. Another class of analgesic drugs that bind tothe μ opioid receptor is the piperidine and phenylpiperidine class ofanalgesics such as meperidine, diphenoxylate, loperamide, fentanyl,sufentanil, alfentanil, and remifentanil.

Included in this invention is a method for producing pharmaceuticalagents with both a low abuse potential and an extended duration ofaction. The method involves conversion, prior to formulation, of abioavailable analgesic drug to a prodrug that is more poorly absorbed byand/or more poorly activates the target tissue. This invention includesbut is not limited to ester prodrug compositions of bioavailable opioidanalgesic agents wherein an alkyl or cyclic alkyl or phenolic or enolichydroxyl group of the drug is covalently linked to an acyl group thathas the following structure

-   -   wherein the values of m and n are independently selected from        the values 0, 1, 2 or 3.    -   Z and X are independently selected from    -   and W is selected from R₁.    -   wherein, R₁, R₂, and R₃ are independently selected from        hydrogen.        -   C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇            cycloalkyl, or amino or guanidino or amidino or carboxy or            acetamido or carbamyl or sulfonate, phosphate or            phosphonate.        -   C₁₋₄ alkoxy.        -   methylenedioxy.        -   hydroxy.        -   carboxy.        -   sulfonate.        -   C₃₋₇ cycloalkyl.        -   aryl unsubstituted or substituted with guanidino or amidino            or carboxy or acetamido or carbamyl or sulfonate, phosphate            or phosphonate.        -   benzyl with the benzene ring unsubstituted or substituted            with guanidino or amidino or carboxy or acetamido or            carbamyl or sulfonate, phosphate or phosphonate.        -   R₁ and R₂ along with the carbon or carbon atoms to which            they are attached form a C₃₋₇ cycloalkyl ring    -   wherein R_(a) and R_(b) are independently selected from        hydrogen.        -   C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇            cycloalkyl.        -   C₃₋₇ cycloalkyl.        -   aryl unsubstituted or substituted with guanidino or amidino            or carboxy or acetamido or carbamyl or sulfonate, phosphate            or phosphonate.        -   benzyl with the benzene ring unsubstituted or substituted            with guanidino or amidino or carboxy or acetamido or            carbamyl or sulfonate, phosphate or phosphonate.    -   wherein R_(e) is selected from hydrogen.        -   C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇            cycloalkyl, or amino or guanidino or amidino or carboxy or            acetamido or carbamyl or sulfonate, phosphate or            phosphonate.        -   aryl unsubstituted or substituted with guanidino or amidino            or carboxy or acetamido or carbamyl or sulfonate, phosphate            or phosphonate.        -   benzyl with the benzene ring unsubstituted or substituted            with guanidino or amidino or carboxy or acetamido or            carbamyl or sulfonate, phosphate or phosphonate.        -   cellulose or a cellulose derivative such as methyl            cellulose, hydroxyethylcellulose or hydroxypropylcellulose            such that one or more hydroxyl groups in the cellulose or            cellulose derivative forms an ester or urethane linkage in            the prodrug.        -   poly(ethylene glycol) or a poly(ethylene glycol) derivative            such as poly(ethylene glycol) methyl ether, poly(ethylene            glycol) ethyl ether, poly(ethylene glycol) carboxymethyl            ether, poly(ethylene glycol) monolaurate such that one or            more of the hydroxyl groups of the poly(ethylene glycol) or            the poly(ethylene glycol) derivative form an ester or            urethane linkage in the prodrug.    -   wherein R_(d) is selected from        -   a polycarboxylic acid such as carboxymethylcellulose or a            derivative thereof, polyacrylic acid or a derivative            thereof, polymethacrylic acid or a derivative thereof such            that one or more of the carboxyl groups of the macromolecule            forms an amide linkage in the prodrug.        -   poly(ethylene glycol) bis(carboxymethyl)ether, or            poly(ethylene glycol) carboxymethyl, methyl ether or similar            carboxylic acid containing poly(ethylene glycol) derivative            such that one or more carboxyl groups of the poly(ethylene            glycol) derivative forms an amide linkage in the prodrug.    -   wherein R_(e), R_(f) and R_(g) are independently selected from        hydrogen.    -   wherein the values of p, and q are independently selected from        the values 0, 1, 2, or 3 wherein R_(h), R_(i), R_(k) and R_(l)        are independently selected from hydrogen.        -   C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇            cycloalkyl, or amino or guanidino or amidino or carboxy or            acetamido or carbamyl or sulfonate, phosphate or            phosphonate.        -   aryl unsubstituted or substituted with a guanidino or            amidino or carboxy or acetamido or carbamyl or sulfonate,            phosphate or phosphonate.        -   benzyl with the benzene ring unsubstituted or substituted            with a guanidino or amidino or carboxy or acetamido or            carbamyl or sulfonate, phosphate or phosphonate R_(h) and            R_(l) along with the carbon to which they are attached form            a C₃₋₇ alkyl ring.        -   R_(k) and R_(l) along with the carbon to which they are            attached form a C₃₋₇ alkyl ring,    -   wherein R_(j) is selected from        -   hydrogen.        -   C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇            cycloalkyl.        -   C₃₋₇ cycloalkyl.        -   Aryl unsubstituted or substituted with a carboxyl or            guanidino or amidino or carboxy or acetamido or carbamyl or            sulfonate, phosphate or phosphonate.        -   benzyl with the benzene ring unsubstituted or substituted            with a guanidino or amidino or carboxy or acetamido or            carbamyl or sulfonate, phosphate or phosphonate.        -   a polycarboxylic acid such as carboxymethylcellulose or a            derivative thereof, polyacrylic acid or a derivative            thereof, polymethacrylic acid or a derivative thereof such            that one or more carboxyl groups in the macromolecule forms            an amide linkage in the prodrug.        -   poly(ethylene glycol) bis(carboxymethyl)ether, or            poly(ethylene glycol) carboxymethyl, methyl ether or similar            carboxylic acid containing poly(ethylene glycol) derivative            such that one or more carboxyl groups of the poly(ethylene            glycol) derivative forms an amide linkage in the prodrug.        -   Y is independently selected from the following:    -   wherein the values of u and v are independently selected from        the values 0, 1, 2 or 3, and the value of r is a value between        10 and 1,000.    -   wherein R4 is independently selected from:        -   Ra.        -   Rb.        -   R_(d).

The compounds of the invention may have chiral centers and may occur asepimeric mixtures, diastereomers, and enantiomers. All suchstereoisomers are included in this invention. When any variable occursrepeatedly in formula I, the definition of that variable is independentof its definition at every other occurrence of that variable.Additionally, combinations of variables and substituents are permissibleonly when they produce stable compounds.

Some of the abbreviations that may appear in this application are asfollows:

Designation Definition

-   -   Boc tert-butyloxycarbonyl    -   tBu tert-butyl    -   Cbz benzyloxycarbonyl    -   DCM dichloromethane    -   DCC N,N′-dicyclohexylcarbodiimide    -   DCU N,N′-dicyclohexylurea    -   DIEA diisopropylethylamine    -   DMAP 4-(dimethylamino)pyridine    -   EtOAc ethyl acetate    -   Glu glutamic acid    -   h hour(s)    -   HOBt 1-hydroxybenzotriazole    -   HPLC high performance liquid chromatography    -   min minute(s)    -   NMR nuclear magnetic resonance    -   rt room temperature    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography

The acyl portion of the prodrug ester is chosen so as to endow theprodrug with i) a low bioavailability and ii) a rate of conversion ofprodrug to drug that results in a desired oscillation in the plasmaconcentration of drug over the dosing interval.

To restrict entry of the prodrug into the blood and/or entry of theprodrug into the central nervous system or otherwise restrict thebioavailability of the prodrug, one chooses a macromolecular acyl group(Mr greater than about 1000), and/or a low molecular weight acyl group(Mr less than about 1000) that contains one or more groups that bear acharge at pH 7, and/or groups that contain multiple hydrogen bond donorsand acceptors such as amide groups.

In cases wherein the prodrug is poorly absorbed into the blood streamafter administration, the rate of conversion of prodrug to drugsubstantially controls the duration and intensity of the effect of thedrug. In cases wherein the prodrug is directly injected into the bloodor it is absorbed into the blood, but does not enter or activate thetarget tissue, the effect of administration of the prodrug also will becontrolled substantially by the rate of conversion of prodrug to drug.

We have discovered how to produce ester prodrugs of alkaloid opioidanalgesics with rates of nonenzymatic hydrolysis at pH 7 compatible witha wide range of dosing frequencies. It is recognized that for some ofthe prodrugs included in this invention, enzymes may contribute to therate of conversion of prodrug to drug. The contribution of suchenzymatically catalyzed conversions to the overall rate of conversion ofprodrug to drug may be roughly estimated from in vitro assessment of theconversion of the drug in presence of digestive enzymes and bloodplasma. Comparative pharmacokinetic studies after administration of drugand prodrug to a patient should yield an accurate estimate of the timedependent conversion of prodrug to drug in the patient. When desirableit should be possible for someone skilled in the art to adjust the rateof nonenzymatic conversion and enzymatically catalyzed conversion ofprodrug to drug by judicious modification of the structure of theprodrug. Moreover, someone skilled in the art should be able toformulate combinations of prodrug derivatives that release the same drugat differents rates so as to produce a desired oscillation in plasmadrug concentration over the dosing interval.

The feasibility of forming enol esters of alkaloid opioids related todihydromorphinone has been demonstrated by Nagase et al. and by Hosztafiet al. These investigators, however, studied neither the hydrolysis ofopioid enol esters nor their suitability as prodrugs.

Esters of the phenolic hydroxyl group of various opioid agonists andantagonists have been studied as prodrugs for increasing the efficiencyof transdermal, sublingual and buccal delivery and masking the bittertaste opioid agonists and antagonists (see for example, Hansen et al.;Stinchcomb et al.; and Hussain et al.).

For enol esters and phenyl esters wherein the alcohol portion of theester is a good leaving group the rate of ester hydrolysis is increasedby increasing the acidity of the carboxyl group of parent carboxylicacid and/or by utilizing an acyl group that contains an appropriateneighboring nucleophilic catalyst such as a carboxylate group that iscapable of facilitating hydrolysis via nucleophilic catalysis asexemplified below. In cases wherein the intrinsic rate of hydrolysis atpH 7 is more rapid than desired, steric and charge effects can beemployed to reduce the rate of hydrolysis at pH 7 as exemplified below.

Listed below by way of example and without limitation are some oxycodoneprodrug compositions included in this invention that have an acyl groupwith structure I.

The zwitterionic character and/or molecular weight of these compoundsendow them with a low bioavailability, relative to that of the drug.

Enol ester prodrugs 1-7 are carboxylic acid derivatives, wherein thefree carboxylate (at pH 7) group facilitates hydrolysis of the enolester and endows the enol ester with a rate of hydrolysis that changeslittle in the pH range 6-8. This effect minimizes intra-individual (overtime) or inter-individual variation in the rate of hydrolysis ofcompounds 1-7 due to variation of the pH within the intestinal lumen. Itis important to note that the disposition of the carboxylate group is animportant determinant of the rate of hydrolysis of it effect on esterhydrolysis (see Table 1). TABLE I Half-Life for the NonenzymaticHydrolysis of Oxycodone Enol Ester Prodrugs at pH 7.0, 37° C.*

R— Half Life* (h)

<0.5

11.4

3.5

6.5

2.4

173

66

6.4

11.3

6.9*Half-life was determined from the first order conversion of prodrug tooxycodone in buffered solution maintained at 37° C. The amount ofprodrug remaining was determined by HPLC wherein the ester wasquantified from measurements of the area under the prodrug peak inchromatograms wherein the absorbance of the ester (typically at 280 nm)was monitored using a diode array detector. Plots of the logarithm ofthe fraction of prodrug remaining versus time were linear as expectedfor a first order# process.

It is important to note that the hydrolysis of alkyl esters with higherpK alcohol leaving groups (such as esters 10-12) is not facilitated bythe presence of a neighboring carboxyl group (See Table II). Weobserved, however, that esters of the 14-hydroxyl group in oxycodone arehydrolyzed rapidly at pH 7. For example we found that the half-life forthe hydrolysis of the 14-acetate ester of oxycodone is ˜20 min at pH 7,37° C., whereas the half-life for hydrolysis of the 6-enolacetate is ˜4days under these conditions. The high rate of hydrolysis of theoxycodone 14-acetate may well reflect intramolecular nucleophilic attackby the neighboring tertiary amino group in oxycodone to form anacylammonium ion intermediate that is rapidly hydrolyzed at pH 7. TABLEII Half-Life for the Nonenzymatic Hydrolysis of Oxycodone 14-EsterProdrugs at pH 7.0, 37° C.* R—

Half life (h) 7.0 2.1 1.9*Half-Life was determined as described in Table I.

Included in this invention is a method to impede intravenous and nasaladministration of hydrolytically treated prodrug tablets or capsulebeads by formulating the prodrugs with an appropriate amount of athickening agent such as hydroxypropylmethylcellulose orcarboxymethylcellulose. Hydrolytic treatment of such ester prodrugformulations to release the drug produces a high viscosity glue-likematerial that would be difficult to administer nasally. Moreover, thismaterial requires dilution to more than 10 mL to easily pass through ahypodermic needle suitable for intravenous administration. Also includedin this invention is a method to add a sufficient amount of a thickeningagent such as hydroxypropylmethylcellulose or carboxymethylcellulose toimpede intravenous and nasal administration of drug and prodrugformulations that are not indicated for these routes of administration.Dissolution for intravenous administration of a drug or prodrug in aformulation containing the thickening agent produces a highly viscousglue-like material that requires dilution to more than 10 mL to easilypass through a hypodermic needle suitable for intravenousadministration. The thickening agent also reduces absorption of drug orprodrug from nasally administered powdered tablets or capsule beads.This reduction may reflect an osmotic effect of the thickening agent.

Ester prodrugs of the invention can be prepared according to the generalprocedures outlined below:

General Procedure for the Preparation of Enol Ester Prodrugs

The free base form of an aldehyde or ketone containing drug at0.0.025-0.5 mol/L is dissolved or suspended in an aprotic polar solventsuch as anhydrous THF or DCM under argon and cooled in a acetone/dry-icebath. A 1.05 molar excess over drug of potassium tBu-OH is added, andthe reaction mixture stirred for 40 min. A 1.0-1.2 molar excess overdrug of the nitrophenyl ester of the carboxylic acid to be esterified bythe enol group of the drug is added via syringe as a 0.025-2.0 M.solution in THF or DCM. After 1-2 h, or when the reaction is complete asjudged by formation of the enol ester and liberation of nitrophenol, thereaction is neutralized by the addition of TFA. If the reactionsolidifies at −78° C., it is allowed to warm to rt before addition ofthe TFA. In cases involving the formation of hemi-esters of certainsymmetrical dicarboxylic acids, one can use the cyclic dicarboxylic acidanhydride in place of a nitrophenyl ester.

The following carbodiimide mediated coupling reactions can also be usedto prepare enol ester prodrugs. The free base form of an aldehyde orketone containing drug at a concentration of 0.025-1.0 M in an aproticpolar solvent such as anhydrous acetonitrile, THF, or DCM is treatedwith a 3-6-fold molar excess of a tertiary amine strong base such as TEAor DIEA for 20-30 min at rt to promote enolate formation. DMAP, DCC, andcarboxylic acid are then added so that the molar ratio DMAP: carboxylicis in the range of 0.5-1.0, the molar ratio DCC:carboxylic acid is inthe range 0.5-1.5, and the molar ratio of carboxylic acid:drug is in therange 2-6.

In cases wherein a low yield is obtained using this procedure, addition,prior to addition of carboxylic acid, of HOBt (in a molar amountapproximately equivalent to the carboxylic acid) may increase the yield.Groups in the prodrug that might interfere with ester formation can beblocked with groups (such as Boc, tBu, and Cbz) that may be removedafter ester formation without significant decomposition of the ester.

General Procedure for the Preparation of Alcohol Ester and Phenyl EsterProdrugs

The above procedure for preparation of enol esters wherein the additionof strong base (to promote enolization) is eliminated may also be usedto prepare alcohol and phenyl ester prodrugs. Additionally, alcoholester prodrug may be prepared by condensing cyclic carboxylic acidanhydrides with drugs containing an alkyl or cycloalkyl hydroxyl groupin pyridine as described in Example 2. It is important to note that i)dicarboxylic acids (such as maleic acid, phthalic acid and succinicacid) that facilely form cyclic anhydrides form unstable phenyl and enolesters; ii) esters of the 14-hydroxyl group of drugs in the14-hydroxymorphinan family that contain a tertiary 17-amino group areunstable unless hydroxide ion catalyzed ester hydrolysis iselectrostatically or sterically impeded; iii) enol ester formation canbe eliminated by forming acid labile ketal and acetal derivatives ofdrugs that contain these groups. One skilled in the art can exploitthese findings together with differential chromatographic properties toconvert a drug containing more than one hydroxyl group to a desired monoester prodrug.

EXAMPLES Example 1 Preparation of pentanedioic acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester(1-4, also designated compound 2) Step A: Preparation of Oxycodone FreeBase (1-1)

Oxycodone (Ig) was dissolved in water (5 mL) and mixed with 30 mL of asaturated sodium bicarbonate solution to produce the free base. Theresulting suspension was extracted with three 70 mL portions of EtOAc.The combined EtOAc extract was washed with 30 mL of saturated sodiumbicarbonate, 30 mL of brine and dried over magnesium sulfate. EtOAc wasremoved under reduced pressure from the resulting solution to yield 785mg of oxycodone free base.

Step B: Preparation of Pentanedioic Acid Mono-Tert-Butyl Ester (1-2)

Potassium tert-butoxide (2.7 g, 24 mmol) was dissolved in 17 mL ofanhydrous THF at rt. After 5 min glutaric anhydride (2.4 g, 21 mmol) wasadded and the resulting suspension stirred for 2 h at rt. The reactionmixture was then quenched with 20 mL of 1 M KHSO₄, extracted with 50 mLof EtOAc, adjusted to pH 2-3 with 1 M KHSO₄ and extracted twice with 50mL EtOAc. The combined extracts were dried over anhydrous magnesiumsulfate, filtered and concentrated to give a yellow oil which waspurified by silica gel flash chromatography (eluent: EtOAc:Hexanes-1:1)to give 1.65 g (35% yield) pure (TLC) 1-2.

Step C: Preparation of pentanedioic acid tert-butyl ester3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-ylester (1-3)

A suspension of oxycodone free base (100 mg, 0.317 mmol) in 1.5 mL ofanhydrous acetonitrile was stirred for 20 min with DIEA (0.2 mL 1.15mmol). DMAP (63 mg, 0.516 mmol) and DCC (112 mg, 0.545 mmol) were thenadded to the stirred suspension. After 5 min 1-2 (150 mg, 0.8 mmol) wasadded, the mixture stirred for 16 h at rt, and the resulting orangesuspension concentrated to an oil under reduced pressure. Theconcentrated mixture was stirred with 6 mL of acetone for 10 min, andthe precipitated DCU removed by filtration. The filtrate wasconcentrated to give a brown oil. HPLC analysis of the oil indicatedthat the primary reaction product was 1-3. The concentrated oil wassubjected to reverse phase C-18 silica gel chromatography using agradient of 25-40% acetonitrile in 0.07% aqueous TFA as eluent.Evaporation of the eluent from the fraction containing 1-3 gave 82 mg(53% yield) of a colorless oil which was greater than >99% pure 1-3(HPLC).

Step D: Preparation of pentanedioic acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (1-4)

1-3 was treated with 0.5 mL of TFA and after 15 min at rt, the TFA wasremoved under reduced pressure to yield>98% pure 1-4 as indicated byHPLC and the ¹H and ¹³C NMR spectra. (As expected for enol ester 1-4,the ¹H NMR spectrum of the product exhibited a resonance for a vinylicproton at C₇ at 5.53 ppm and the ¹³C NMR spectrum of the productexhibited no resonance for a ketonic carbonyl carbon atom in the regionof 207 ppm.)

Example 2 Preparation of phthalic acidmono-(3-methoxy-4,5α-epoxy-17-methylmorphinan-6-one-14-yl) ester (2-1,also designated compound 10)

A solution comprised of oxycodone free base, 1-1, (63 mg, 0.2 mmol),phthalic anhydride (1.185 g, 8.0 mmol) and DMAP (24 mg, 0.2 mmol) in 10mL of pyridine was stirred in an oil bath at 50-55° C. for 24 h andconcentrated under reduced pressure. The residue was subjected to silicagel flash chromatography with a 5%-20% methanol in dichloromethanegradient. The fraction containing 2-1 was collected and concentratedunder reduced pressure. HPLC indicated that the fraction was 60% pure.The concentrated fraction was subjected to another silica gel flashchromatography using a gradient of 0-20% methanol in dichloromethane aseluent to yield a fraction containing 32 mg (35% yield) of 96% pure(HPLC) 2-1, which was further purified by HPLC. The 1H and ¹³C NMRspectra verified the structure of 2-1 as a hydrogen phthalate ester ofthe 14-hydroxyl group of oxycodone. (The absence of a 1H resonance inthe region of 5.5-6 ppm for a C7 vinylic proton, and the presence of a13C resonance at 207.5 ppm for the C6 carbonyl group excluded thepresence of an enol ester linkage in 2-1.)

Example 3 Preparation of 2-(benzyloxycarbonylamino)-pentanedioic acid1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (3-2, also designated compound 1) Step A: Preparation of2-(benzyloxycarbonylamino)-pentanedioic acid 5-tert-butyl ester1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (3-1)

A solution comprised of oxycodone free base, 1-1, (517 mg, 1.64 mmol),DIEA (1.5 mL, 8.6 mmol) in 9 mL of anhydrous acetonitrile was stirred atrt for 20 min and mixed with a solution containing DMAP (400 mg, 3.3mmol), DCC (1.01 g, 4.1 mmol), and HOBt (440 mg, 3.3 mmol) in 6 mL ofanhydrous acetonitrile. Cbz-L-Glu(OtBu)-OH (1.1 g, 3.3 mmol) was thenadded to the combined solutions. The mixture was stirred for 45 h at rt,precipitated DCU removed by filtration, and the solution concentratedunder reduced pressure to give a dark-brown oil. HPLC analysis indicatedthat 39% of the oxycodone had been converted to 3-1. The brown oilcontaining crude 3-1 was dissolved in 20 mL of acetone, cooled in an icebath for 2 h, and filtered to remove precipitated DCU. The filtrate wasconcentrated to dryness, and subjected to flash chromatography using agradient of 0-10% methanol in DCM. The fractions containing 3-1 werecombined and concentrated to dryness. The residue was treated with 20 mLacetone and filtered to remove precipitated DCU. The filtrate wasconcentrated to dryness under reduced pressure to yield partiallypurified 3-1.

Step B: Preparation of 2-(benzyloxycarbonylamino)-pentanedioic acid1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (3-2)

The partially purified 3-1 from Step B was treated with 4 mL TFA in 2 mLDCM at rt for 10 min, dried immediately, and twice taken up in 10 mLacetonitrile and evaporated to dryness. The resulting residue wassubjected to C-18 silica gel chromatography using a 20-40% gradient ofacetonitrile in 0.07% aqueous TFA as eluent. Fractions containing pure3-1 were combined to yield 105 mg (11% yield) of >99% pure (HPLC) 3-2.

Example 4 Preparation of Fumaric Acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (4-3) Step A: Preparation of Fumaric Acid Ethyl Ester tert-butylester (4-1)

To a solution of fumaric acid mono-ethyl ester (721 mg, 5 mmol) andtert-butanol (0.938 mL, 10 mmol) in 10 mL of DCM was added DMAP (122 mg,1 mmol) followed by DCC (2.06 g, 10 mmol). The resulting mixture wasstirred at rt for 16 h, taken to dryness under reduced pressure, stirredovernight with 50 mL acetone and filtered to remove DCU. The resultingfiltrate was concentrated under reduced pressure, and the residue takenup in EtOAc. The EtOAc was washed twice with 30 mL 0.1 M KHSO₄, and oncewith 30 mL saturated NaHCO₃ and once with 30 mL of brine. The resultingEtOAc solution was treated with charcoal and dried over magnesiumsulfate, concentrated under reduced pressure, and subjected to silicagel flash chromatography using a gradient of 0-15% EtOAc in hexanes aseluent to give essentially pure (one peak on HPLC) 4-1 (350 mg, 35%yield).

Step B: Preparation of Fumaric Acid mono-tert-butyl ester (4-2)

4-1 (340 mg, 1.7 mmol) was stirred for 1 h at rt with a solutioncomprised of 4 mL THF, and 4 mL of a solution containing 1 M NaOH and 1M LiCl. The resulting mixture was acidified to pH 3-4 with 1 M KHSO₄ andextracted twice with 30 mL of EtOAc. The extract was washed with 30 mLof brine, dried over magnesium sulfate, and concentrated under reducedpressure. The resulting material was subjected to silica gel flashchromatography using a gradient of 5-10% methanol in DCM to yield 240 mg(82% yield) of 4-2.

Step C: Preparation of fumaric acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (4-3)

Oxycodone free base, 1-1, (13 mg, 0.04 mmol) in 0.5 mL acetonitrile wasstirred with TEA (0.034 mL 0.24 mmol) for 30 min at rt. DMAP (15 mg,0.12 mmol) and DCC (25 mg, 0.12 mmol) were then added to the solutionfollowed by a solution comprised of 4-2 (41 mg, 0.24 mmol) in 1 mL ofacetonitrile. The resulting mixture was stirred for 16 h andconcentrated under reduced pressure. The resulting residue was stirredwith 4 mL of acetone for 30 min, the precipitated DCU removed byfiltration, and the acetone removed under reduced pressure. The residuewas treated with 0.8 mL of TFA (5 min at rt) to remove the tert-butylgroup. The TFA was then removed under reduced pressure and the resultingresidue purified by HPLC on a C-18 column eluted with 20% acetonitrilein 0.07% aqueous TFA to yield fraction containing essentially pure 4-3.

Example 5 Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carbonylimidodiacetic acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (5-4, also designated compound 5) Step A: Poly(ethylene glycol),Mr 2,000, methyl ether, nitrophenyl carbonate (5-1)

10 g (5 mmol) of poly(ethylene glycol), Mr 2,000, methyl ether wasboiled with 200 mL of toluene and 100 mL of solvent distilled off toremove water. The solution was cooled to rt, 10 mL (61 mmol) of DIEA and10 g (50 mmol) of nitrophenyl chloroformate added, and the mixturestirred overnight at 55° C. The reaction mixture was then concentratedunder reduced pressure. The residue was taken up in DCM, and purified byprecipitation from DCM with ethyl ether to yield 10 g of 5-1 (92%).

Step B: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carbonylimidodiacetic acid (5-2)

5-1 was added to a stirred mixture of 0.666 g (5 mmol) iminodiaceticacid, 1.9 mL (11.5 mmol) DIEA, and 20 mL of DCM. After 12 h, reversephase HPLC of an acidified aliquot of the reaction mixture indicatedessentially complete release of p-nitrophenol and consumption of 5-1.The reaction mixture was filtered, and the filtrate concentrated underreduced pressure. Ethyl ether (200 mL) was added to the concentrate toprecipitate the product. 1 N HCl (50 mL) was added to dissolve thesolid. After extraction the aqueous phase with DCM, the DCM wasconcentrated under reduced pressure. Addition of ethyl ether to the DCMconcentrate yielded 5-2 (0.446 g, 45%).

Step C: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carbonyliminodiacetic anhydride (5-3)

DCC (28 mg, 0.25 mmol) was added to 5-2 (430 mg, 0.2 mmol) in 3 mL DCM.After stirring the solution for 4 h, the DCU was removed by filtrationto yield a DCM solution of 5-3 which was used in Step D without furtherpurification.

Step D: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carbonyliminodiacetic acidmono-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (5-4)

K-OtBu (28 mg, 0.25 mmol) was added to a stirred suspension of 1-1 (65mg, 0.21 mmol) in 2 mL DCM under argon at −78° C. in an acetone/dry icebath. After 40 min, the DCM solution of 5-3 from Step C (which was atrt) was added via syringe to the stirred solution of 1-1 under argon inthe acetone/dry ice bath. After one hour the reaction mixture wasbrought to rt and neutralized with TFA. The resulting DCM solution waswashed with 0.1% aqueous TFA and concentrated under reduced pressure.Purified product, 5-4, was obtained by precipitation of the DCMconcentrate with ethyl ether.

Example 6 Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglutamic acid1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (6-4, also designated compound 4) Step A: Preparation ofpoly(ethylene glycol), Mr 2000, methyl ether, N-carbonylglutamic acid5-tert-butyl ester (6-1)

5-1 (1 g, 0.46 mmol) was added to a stirred suspension of 1.02 g (5mmol) 2-aminopentanedioic acid 5-tert-butyl ester in 7.5 mL of 0.333 MNaOH at rt. The solution turned yellow concomitant with dissolution of5-1. After 45 min, reverse phase HPLC indicated essentially completeconsumption of 5-1 and liberation ofp-nitrophenol. The reaction mixturewas acidified to pH 1 with 1 N HCl, and extracted with DCM. The DCM waswashed with 0.1 N HCl and concentrated under reduced pressure. Additionof ethyl ether to the DCM concentrate resulted in precipitation of 450mg (0.202 mmol, 44%) of the desired product (6-1).

Step B: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglutamic acid 5-tert-butyl ester, 1-p-nitrophenyl ester (6-2)

6-1 (0.45 g, 0.20 mmol) and p-nitrophenol (36 mg, 0.26 mmol) weredissolved in 1 mL of DCM. The solution was cooled in an ice water bath;after which time DCC (53 mg. 0.26 mmol) was added. After 10 minutes ofstirring in the ice water bath, the solution was removed from the icewater bath and stirred overnight at rt. The resulting reaction mixturewas filtered to remove DCU. The DCU precipitate was washed with 5 mL ofDCM, and the DCM solutions were combined and concentrated under reducedpressure. The product (6-2) was purified from the DCM concentrate byprecipitation with ethyl ether to yield 168 mg (36%) of 6-2.

Step C: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglutamic acid 5-tert-butyl ester,1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (6-3)

K-OtBu (10 mg, 0.0.086 mmol) was added to a stirred suspension of 1-1(23 mg, 0.073 mmol) in 1 mL DCM under argon at −78° C. in an acetone/dryice bath. After 40 min, 168 mg (0.071 mmol) of 6-2 in 1 mL DCM (whichwas at rt) was added via syringe to the stirred solution of 1-1 underargon in the acetone/dry ice bath. After one hour, the reaction mixturewas neutralized with TFA. The resulting DCM solution was washed with0.1% aqueous TFA and concentrated under reduced pressure. The product,6-3, was purified by precipitation of DCM concentrates of 5-4 with ethylether.

Step D: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglutamic acid1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (6-4)

5-4 was dissolved in neat TFA at rt, after 15 min the TFA was removedunder reduced pressure to yield 6-4, which was purified by dissolutionin DCM and precipitation with ethyl ether.

Example 7 Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglycine1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (7-3) Step A: Preparation of poly(ethylene glycol), Mr 2,000,methyl ether, N-carbonylglycine (7-1)

5-1 (1 g, 0.46 mmol) was added to a solution of glycine (0.375 g, 5mmol) in 5 mL of 0.5 N NaOH. The solution turned yellow concomitant withdissolution of 1. After 45 min reverse phase HPLC of an acidifiedaliquot of the reaction mixture indicated essentially completeconsumption of 5-1 and release of p-nitrophenol. The reaction mixturewas acidified to pH 1 with 1 N HCl and extracted three times with 5 mLDCM. The combined DCM extract was washed with water and concentratedunder reduced pressure. Addition of ethyl ether resulted inprecipitation of 436 mg (0.207 mmol, 45%) of 7-1.

Step B: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglycine 1-p-nitrophenyl ester (7-2)

7-1 (436 mg, 0.21 mmol) andp-nitrophenol (37 mg 0.27 mmol) weredissolved in 1 mL of DCM. The solution was cooled in an ice water bathand DCC (55 mg, 0.27 mmol) was added. After 10 minutes of stirring inthe ice water bath, the solution was stirred overnight at rt. Thesolution was filtered to remove the DCU and the DCU precipitate washedwith 5 mL of DCM. The DCM solutions combined, concentrated under reducedpressure and the product precipitated with ethyl ether to yield 130 mg(28%) of 7-2.

Step C: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,N-carbonylglycine1-(3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester (7-3)

K-OtBu (28 mg, 0.25 mmol) was added to a stirred suspension of 1-1 (65mg, 0.21 mmol) in 2 mL DCM under argon at −78° C. in an acetone dry icebath. After 40 min, 130 mg 7-2 in 0.5 mL DCM (which was at rt) was addedvia syringe to the stirred solution of 1-1 under argon in theacetone/dry ice bath. After one hour, the reaction mixture wasneutralized with TFA. The resulting DCM solution was washed with 0.1%aqueous TFA and concentrated under reduced pressure. The product, 7-3,was purified by precipitation of DCM concentrates of 7-3 with ethylether.

Example 8 Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carboxy((3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester) methyl ether (8-3, also designated compound 8) Step A:Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carboxymethyl ether (8-1)

50 g of poly(ethylene glycol), Mr 2,000, methyl ether (25 mmol) in 750mL of toluene was boiled and 200 mL solvent distilled off to removewater. The solution was cooled to rt and 4.5 g of KOtBu in 50 mL oft-butanol was added. The resulting mixture was stirred for 1 h at rt and16 mL of ethyl bromoacetate added. The resulting solution was heated toreflux for 0.75 h, stirred at rt for 18 h, stirred with Celite andfiltered. The reaction solvent was removed under reduced pressure, theresidue taken up in 200 mL DCM and precipitated with 3.3 L of ethylether to yield 40 g of the ethyl ester derivative of 8-1. This materialwas stirred with 400 mL of 1 N sodium hydroxide for 4 h at rt, cooled inan ice water bath, acidified to pH 1 with 2 N HCl, and extracted twicewith 200 mL of DCM. The DCM extract was concentrated under reducedpressure to approximately 50 mL, and added to 400 mL of ethyl ether. Theresulting precipate was washed with ethyl ether and dried under reducedpressure to yield 37 g (72%) of 8-1.

Step B: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carboxy (p-nitophenyl ester) methyl ether (8-2)

p-Nitrophenol (0.42 g, 3 mmol) was dissolved in a solution of 8-1 (5 g,2.5 mmol) in 20 mL of DCM, and cooled in an ice bath. DCC (0.62 g, 3)was then added with stirring. After 10 min the solution was removed fromthe ice water bath and stirred overnight at room temperature. Thereaction mixture was filtered to remove DCU and the filtrate added to400 mL of ethyl ether. The resulting precipate was collected, washedwith ethyl ether and dried under reduced pressure to yield 3.4 g (˜62%)of 8-1.

Step C: Preparation of poly(ethylene glycol), Mr 2,000, methyl ether,carboxy((3-methoxy-14-hydroxy-6,7-didehydro-4,5α-epoxy-17-methylmorphinan-6-yl)ester) methyl ether 8-3

K-OtBu (59 mg, 0.52 mmol) was added to a stirred suspension of 1-1 (141mg, 0.45 mmol) in 6 mL DCM under argon at −78° C. in an acetone/dry icebath. After 40 min, 1 g (0.5 mmol) of 8-1 in 5 mL DCM (which was at rt)was added via syringe to the stirred solution of 1-1 under argon in theacetone/dry ice bath. The dry ice bath was removed and the stirredreaction mixture was allowed to come to rt over a period of 1 h. Thereaction mixture was then neutralized with neat TFA, washed with 0.1%aqueous TFA, and concentrated under reduced pressure. The product, 8-3,was purified by precipitation of DCM concentrates of 8-3 with ethylether.

Example 9 Binding Affinity of Prodrug of an Analgesic Drug v. theAnalgesic Drug

Receptor Interactions

Interactions of a prodrug of oxycodone with the μ, opioid receptors wereassessed wherein receptor affinity was determined from inhibition ofradio labeled ligand binding to membranes from C6 rat glioma cellsexpressing recombinant μ (rat) opioid receptor. Opioid-agonist activitywas evaluated from the ability of the test article to stimulate[³⁵S]-GTP's binding. The data in the Table reveal that compound 1, aprodrug of oxycodone, has a substantially lower affinity for the μreceptor than does oxycodone. It is important to note that the affinityof compound 1 for the μ receptor may well be lower than that indicatedby the measured K_(i), since partial conversion of prodrug to oxycodoneduring the assay may have occurred.

Interactions of Compound 1 and Oxycodone with Opioid Receptors

Affinity Agonist Activity Receptor Opioid K_(i) (μM) EC₅₀ (μM) μCompound 1 1.21 ± 0.18 3.38 ± 0.29 μ Oxycodone 0.21 ± 0.01 0.85 ± 0.15

Conclusions: This shows that the prodrug of oxycodone, compound 1 has alower binding affinity for the μ opioid receptor than the analgesic drugoxycodone.

Example 10 Effect of Pancreatic Enzymes and Pepsin on the Rate ofConversion of Prodrug to Drug

The half-lives for hydrolysis of prodrug to drug listed in the followingtable indicate that pancreatic enzymes do not markedly effect theliberation of oxycodone from compounds 4 and 5, whereas the release ofoxycodone from compound 8 is markedly enhanced by pancreatic enzymes.

Effect of Pancreatin (0.5 mg/mL at 37° C., pH 7.4) and Pepsin (2 mg/mLat 37° C., pH 2) on the Half-Life for Release of Oxycodone from Prodrugs4,5 and 8

Half-Life for Hydrolysis (h) Compound no pancreatin plus pancreatin pluspepsin 4 5.5 4.8 105 5 11 8 103 8 6.9 1

Conclusions: These data indicate that it is possible to identifyprodrugs which either resist or are susceptible to the action ofpancreatic enzymes. By using one or two or more prodrugs with differenthalf-lives in the digestive tract, it should be possible for one skilledin the art to obtain a desired oscillation in oxycodone concentration inthe blood over the dosing interval.

1. A prodrug comprising an opiate covalently linked to a substituent,wherein the prodrug has a lower binding affinity to a μ opoid receptorthan a non-linked opiate, and wherein the opiate is selected from thegroup consisting of oxymorphone; morphine; nalbuphine; butorphanol;nalorphine; hydrocodone; pentazocine; and hydromorphone.
 2. The prodrugof claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 3. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 4. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 5. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof, wherein R1 is selected from the group consisting of: a.hydrogen; b. C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇cycloalkyl, or amino or guanidino or amidino or carboxy or acetamido orcarbamyl or sulfonate, or phosphate or phosphonate; c. C₁₋₄ alkoxy; d.methylenedioxy; e. hydroxy; f. carboxy; g. sulfonate; h. C₃₋₇cycloalkyl; i. aryl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate; and j. benzyl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate.
 6. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 7. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 8. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 9. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.
 10. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof, wherein R₁ is selected from the group consisting of: a.hydrogen; b. C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇cycloalkyl, or amino or guanidino or amidino or carboxy or acetamido orcarbamyl or sulfonate, or phosphate or phosphonate; c. C₁₋₄ alkoxy; d.methylenedioxy; e. hydroxy; f. carboxy; g. sulfonate; h. C₃₋₇cycloalkyl; i. aryl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate; and j. benzyl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate.
 11. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof, wherein R1 is selected from the group consisting of: a.hydrogen; b. C₁₋₄ alkyl unsubstituted or substituted with CH₃ or C₃₋₇cycloalkyl, or amino or guanidino or amidino or carboxy or acetamido orcarbamyl or sulfonate, or phosphate or phosphonate; c. C₁₋₄ alkoxy; d.methylenedioxy; e. hydroxy; f. carboxy; g. sulfonate; h. C₃₋₇cycloalkyl; i. aryl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate; and j. benzyl, unsubstituted or substituted with guanidino,amidino, carboxy, acetamido, carbamyl, sulfonate, phosphate, orphosphonate.
 12. The prodrug of claim 1, wherein the substituent is

wherein R_(D) is the opiate or a pharmaceutically acceptable saltthereof.